Circulating tumor DNA (ctDNA) in the era of personalized cancer therapy

  • Fatemeh Khatami
  • Seyed Mohammad Tavangar
Review Article


The heterogeneity of tumor is considered as a major difficulty to victorious personalized cancer medicine. There is an extremeneed of consistent response evaluation for in vivo tumor heterogeneity anditscoupledconflict mechanisms. In this occasion researchers will be able to keep pace withpredictive, preventive, personalized, and Participatory (P4) medicine for cancer managements. In fact tumor heterogeneity is a central part of cancer evolution,soin order to progress in understanding of the dynamics within a tumor some diagnostic apparatus should be improved. Latest molecular techniques like Next generation Sequencing (NGS) and ultra-deep sequencing could disclose some clones within a liquid tumor biopsy which mainly responsible of treatment resistance. Circulating tumor DNA (ctDNA) as a main component of liquid biopsy is agifted biomarker for cancer mutation tracking as well as profiling. Personalized medicine facilitate learning regarding to genetic pools of tumor and their possible respond to treatment which could be much easier by using of ctDNA.With this information, cliniciansarelooking forward to find the best strategies for prevention, screening, and treatment in the way of precision medicine. Currently, numerous clinical efficacy of such informative improved treatment are in hand. Here we represent the review of plasma-derived ctDNA studies use in personalized cancer managements.


Circulating tumor DNA (ctDNA) Personalized medicine Cancer 



Anaplastic Thyroid Cancer


Aromatase inhibitor


Breast Cancer


Cancer Personalized Profiling by deep Sequencing


Colorectal cancers


Circulating Tumor DNA


Circulating Tumor Cells


Droplet Digital PCR


Epidermal growth factor receptor tyrosine kinase inhibitors


Epidermal growth factor receptor


Estrogen receptor alpha


U.S. Food and Drug Administration


Human epidermal growth factor receptor 2


Kirsten Rat Sarcoma Viral Oncogene Homolog


Metastatic colorectal cancer


Minimal residual disease


Medularlly Thyroid Cancer


Non-Small Cell Lung Cancer Research


Next-generation sequencing


Progression free survival


Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha


Phosphatidylinositol-4,5-bisphosphate 3-kinase


Platelet-derived growth factor receptor alpha



Special thanks to Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.

Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author.

Authors’ contributions

Professor Seyed Mohammad Tavangar made substantial contributions to conception and design, supervision, acquisition of data, and interpretation of data. Mrs. Fatemeh Khatami had been involved in drafting the manuscript or revising it critically for important intellectual content.


This article was a part of a larger project which was granted by the National Institute for Medical Research Development (NIMAD, Grant number: 957222).

Compliance with ethical standards

Ethics approval and consent to participate

This manuscript does not report on or involve the use of any animal or human data or tissue, so ethical approval is not applicable in this section.

Consent for publication

This review article does not contain data from any individual person; consequently the consent for publication is “Not applicable” in this section.

Competing interests

All authors declare that they have no competing interests” in this section.


  1. 1.
    Larijani B, Shirzad M, Mohagheghi M, Haghpanah V, Mosavi-Jarrahi A, Tavangar S, et al. Epidemiologic analysis of the Tehran cancer institute data system registry (TCIDSR). Asian Pac J Cancer Prev. 2004;5(1):36–9.PubMedGoogle Scholar
  2. 2.
    Haghpanah V, Soliemanpour B, Heshmat R, Mosavi-Jarrahi A, Tavangar S, Malekzadeh R, et al. Endocrine cancer in Iran: based on cancer registry system. Indian J Cancer. 2006;43(2):80–5.PubMedGoogle Scholar
  3. 3.
    Underhill HR, Kitzman JO, Hellwig S, Welker NC, Daza R, Baker DN, et al. Fragment length of circulating tumor DNA. PLoS Genet. 2016;12(7):e1006162.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11(6):426–37.PubMedGoogle Scholar
  5. 5.
    Stroun M, Anker P. Nucleic acids spontaneously released by living frog auricles. Biochem J. 1972;128(3):100P.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Stroun M, Lyautey J, Lederrey C, Olson-Sand A, Anker P. About the possible origin and mechanism of circulating DNA: apoptosis and active DNA release. Clin Chim Acta. 2001;313(1):139–42.PubMedGoogle Scholar
  7. 7.
    Anker P, Stroun M, Maurice PA. Spontaneous release of DNA by human blood lymphocytes as shown in an in vitro system. Cancer Res. 1975;35(9):2375–82.PubMedGoogle Scholar
  8. 8.
    Rogers JC, Boldt D, Kornfeld S, Skinner SA, Valeri CR. Excretion of deoxyribonucleic acid by lymphocytes stimulated with phytohemagglutinin or antigen. Proc Natl Acad Sci. 1972;69(7):1685–9.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Diaz Jr LA, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014;32(6):579–86.Google Scholar
  10. 10.
    Hamakawa T, Kukita Y, Kurokawa Y, Miyazaki Y, Takahashi T, Yamasaki M, et al. Monitoring gastric cancer progression with circulating tumour DNA. Br J Cancer. 2015;112(2):352.PubMedGoogle Scholar
  11. 11.
    Tavangar SM, Larijani B, Mahta A, Hosseini SMA, Mehrazine M, Bandarian F. Craniopharyngioma: a clinicopathological study of 141 cases. Endocr Pathol. 2004;15(4):339–44.PubMedGoogle Scholar
  12. 12.
    Pantel K, Alix-Panabières C. Real-time liquid biopsy in cancer patients: fact or fiction? Cancer Res. 2013;73(21):6384–8.PubMedGoogle Scholar
  13. 13.
    Costs AA. Outcomes comparison of tissue and blood based biopsies for the purpose of biomarker testing. Value Health. 2016;19(3):A143–A4.Google Scholar
  14. 14.
    Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013;10(8):472–84.PubMedGoogle Scholar
  15. 15.
    Fisher R, Pusztai L, Swanton C. Cancer heterogeneity: implications for targeted therapeutics. Br J Cancer. 2013;108(3):479.PubMedPubMedCentralGoogle Scholar
  16. 16.
    X-x S, Yu Q. Intra-tumor heterogeneity of cancer cells and its implications for cancer treatment. Acta Pharmacol Sin. 2015;36(10):1219.Google Scholar
  17. 17.
    Marusyk A, Polyak K. Tumor heterogeneity: causes and consequences. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer. 2010;1805(1):105–17.Google Scholar
  18. 18.
    Murtaza M, Dawson S-J, Pogrebniak K, Rueda OM, Provenzano E, Grant J, et al. Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer. Nat Commun. 2015;6:8760.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Malapelle U, de-Las-Casas CM, Rocco D, Garzon M, Pisapia P, Jordana-Ariza N, et al. Development of a gene panel for next-generation sequencing of clinically relevant mutations in cell-free DNA from cancer patients. Br J Cancer. 2017;116(6):802–10.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Bennett CW, Berchem G, Kim YJ, El-Khoury V, Cell-free DNA. Next-generation sequencing in the service of personalized medicine for lung cancer. Oncotarget. 2016;7(43):71013.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Cani AK, Hovelson DH, Demirci H, Johnson MW, Tomlins SA, Rao RC. Next generation sequencing of vitreoretinal lymphomas from small-volume intraocular liquid biopsies: new routes to targeted therapies. Oncotarget. 2017;8(5):7989–98.PubMedGoogle Scholar
  22. 22.
    Siravegna G, Marsoni S, Siena S, Bardelli A. Integrating liquid biopsies into the management of cancer. Nat Rev Clin Oncol. 2017;14(9):531–48.PubMedGoogle Scholar
  23. 23.
    Gerdes L, Iwobi A, Busch U, Pecoraro S. Optimization of digital droplet polymerase chain reaction for quantification of genetically modified organisms. Biomolecular detection and quantification. 2016;7:9–20.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Jovelet C, Madic J, Remon J, Honoré A, Girard R, Rouleau E, et al. Crystal digital droplet PCR for detection and quantification of circulating EGFR sensitizing and resistance mutations in advanced non-small cell lung cancer. PLoS One. 2017;12(8):e0183319.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Schmitt MW, Kennedy SR, Salk JJ, Fox EJ, Hiatt JB, Loeb LA. Detection of ultra-rare mutations by next-generation sequencing. Proc Natl Acad Sci. 2012;109(36):14508–13.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Shu Y, Wu X, Tong X, Wang X, Chang Z, Mao Y, et al. Circulating tumor DNA mutation profiling by targeted next generation sequencing provides guidance for personalized treatments in multiple Cancer types. Sci Rep. 2017;7.1:583. Scholar
  27. 27.
    Bratman SV, Newman AM, Alizadeh AA, Diehn M. Potential clinical utility of ultrasensitive circulating tumor DNA detection with CAPP-Seq. Taylor Francis; 2015.Google Scholar
  28. 28.
    Chaudhuri A, Lovejoy A, Chabon J, Newman A, Stehr H, Say C, et al. CAPP-Seq circulating tumor DNA analysis for early detection of tumor progression after definitive radiation therapy for lung Cancer. International journal of radiation oncology• biology. Physics. 2016;96(2):S41–S2.Google Scholar
  29. 29.
    Mandel P. Les acides nucleiques du plasma sanguin chez l'homme. CR Acad Sci Paris. 1948;142:241–3.Google Scholar
  30. 30.
    Komatsubara KM, Sacher AG. Circulating Tumor DNA as a Liquid Biopsy: Current Clinical Applications and Future Directions. Oncology (Williston Park, NY). 2017;31(8).Google Scholar
  31. 31.
    Leon S, Shapiro B, Sklaroff D, Yaros M, Free DNA. In the serum of cancer patients and the effect of therapy. Cancer Res. 1977;37(3):646–50.PubMedGoogle Scholar
  32. 32.
    Stroun M, Anker P, Maurice P, Lyautey J, Lederrey C, Beljanski M. Neoplastic characteristics of the DNA found in the plasma of cancer patients. Oncology. 1989;46(5):318–22.PubMedGoogle Scholar
  33. 33.
    Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO, Hesch R-D, et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res. 2001;61(4):1659–65.PubMedGoogle Scholar
  34. 34.
    Anker P, Stroun M, Maurice PA. Spontaneous extracellular synthesis of DNA released by human blood lymphocytes. Cancer Res. 1976;36(8):2832–9.PubMedGoogle Scholar
  35. 35.
    Diehl F, Li M, Dressman D, He Y, Shen D, Szabo S, et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci U S A. 2005;102(45):16368–73.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Mouliere F, Rosenfeld N. Circulating tumor-derived DNA is shorter than somatic DNA in plasma. Proc Natl Acad Sci. 2015;112(11):3178–9.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Allis CD, Jenuwein T, Reinberg D. Epigenetics: CSHL Press; 2007.Google Scholar
  38. 38.
    Abbott DW, Ivanova VS, Wang X, Bonner WM, Ausió J. Characterization of the stability and folding of H2A. Z chromatin particles implications for transcriptional activation. J Biol Chem. 2001;276(45):41945–9.PubMedGoogle Scholar
  39. 39.
    Anderson J, Thåström A, Widom J. Spontaneous access of proteins to buried nucleosomal DNA target sites occurs via a mechanism that is distinct from nucleosome translocation. Mol Cell Biol. 2002;22(20):7147–57.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Jansen A, Verstrepen KJ. Nucleosome positioning in Saccharomyces cerevisiae. Microbiol Mol Biol Rev. 2011;75(2):301–20.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Snyder MW, Kircher M, Hill AJ, Daza RM, Shendure J. Cell-free DNA comprises an in vivo nucleosome footprint that informs its tissues-of-origin. Cell. 2016;164(1):57–68.PubMedPubMedCentralGoogle Scholar
  42. 42.
    genomics WDC. A nucleosome footprint reveals the source of cfDNA. Nat Rev Genet. 2016;17(3):125.Google Scholar
  43. 43.
    Ma X, Zhu L, Wu X, Bao H, Wang X, Chang Z, et al. Cell-free DNA provides a good representation of the tumor genome despite its biased fragmentation patterns. PLoS One. 2017;12(1):e0169231.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Fleischhacker M, Schmidt B. Circulating nucleic acids (CNAs) and cancer—a survey. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer. 2007;1775(1):181–232.Google Scholar
  45. 45.
    Yong E. Cancer biomarkers: written in blood. Nature. 2014;511:524–6.PubMedGoogle Scholar
  46. 46.
    Heidary M, Auer M, Ulz P, Heitzer E, Petru E, Gasch C, et al. The dynamic range of circulating tumor DNA in metastatic breast cancer. Breast Cancer Res. 2014;16(4):421.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Guo N, Lou F, Ma Y, Li J, Yang B, Chen W, et al. Circulating tumor DNA detection in lung cancer patients before and after surgery. Sci Rep. 2016;6Google Scholar
  48. 48.
    Wei Z, Wang W, Zitan Shu XZ, Zhang Y. Correlation between circulating tumor DNA levels and response to tyrosine kinase inhibitors (TKI) treatment in non-small cell lung Cancer. Medical science monitor: international medical journal of experimental and clinical research. 2017;23:3627–34.Google Scholar
  49. 49.
    Sacher AG, Paweletz C, Dahlberg SE, Alden RS, O’Connell A, Feeney N, et al. Prospective validation of rapid plasma genotyping for the detection of EGFR and KRAS mutations in advanced lung cancer. JAMA oncology. 2016;2(8):1014–22.PubMedPubMedCentralGoogle Scholar
  50. 50.
    af Hällström TM, Puhka M, Kallioniemi O. Circulating tumor DNA in early-stage breast cancer: personalized biomarkers for occult metastatic disease and risk of relapse? EMBO Molecular Medicine. 2015;7(8):994–5.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Khatami F, Aghayan HR, Sanaei M, Heshmat R, Tavangar SM, Larijani B. The potential of circulating tumor cells in personalized management of breast cancer: a systematic review. Acta Medica Iranica. 2017;55(3):175–93.PubMedGoogle Scholar
  52. 52.
    Olsson E, Winter C, George A, Chen Y, Howlin J, Tang MHE, et al. Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease. EMBO molecular medicine. 2015;7(8):1034–47.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early-and late-stage human malignancies. Science translational medicine. 2014;6(224):224ra24-ra24.Google Scholar
  54. 54.
    Leary RJ, Kinde I, Diehl F, Schmidt K, Clouser C, Duncan C, et al. Development of personalized tumor biomarkers using massively parallel sequencing. Sci Transl Med 2010;2(20):20ra14-20ra14.Google Scholar
  55. 55.
    Dawson S-J, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin S-F, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368(13):1199–209.PubMedGoogle Scholar
  56. 56.
    Murtaza M, Dawson S-J, Tsui DW, Gale D, Forshew T, Piskorz AM, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013;497(7447):108.PubMedGoogle Scholar
  57. 57.
    Sidransky D. Nucleic acid-based methods for the detection of cancer. Science. 1997;278(5340):1054–8.PubMedGoogle Scholar
  58. 58.
    Heitzer E, Auer M, Ulz P, Geigl JB, Speicher MR. Circulating tumor cells and DNA as liquid biopsies. Genome medicine. 2013;5(8):73.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Heitzer E, Ulz P, Geigl JB. Circulating tumor DNA as a liquid biopsy for cancer. Clin Chem. 2015;61(1):112–23.PubMedGoogle Scholar
  60. 60.
    Mohammadi-asl J, Larijani B, Khorgami Z, Tavangar SM, Haghpanah V, Kheirollahi M, et al. Qualitative and quantitative promoter hypermethylation patterns of the P16, TSHR, RASSF1A and RARβ2 genes in papillary thyroid carcinoma. Med Oncol. 2011;28(4):1123–8.PubMedGoogle Scholar
  61. 61.
    Garcia-Murillas I, Beanney M, Epstein M, Howarth K, Lawson A, Hrebien S, et al. Abstract 2743: comparison of enhanced tagged-amplicon sequencing and digital PCR for circulating tumor DNA analysis in advanced breast cancer. Cancer Res. 2017;77(13 Supplement):2743.Google Scholar
  62. 62.
    Tzanikou E, Markou A, Politaki E, Koytsodontis G, Psyrri A, Georgoulias V, et al. Abstract 1725: Detection of <em>ESR1</em> D538G mutation in circulating tumor cells (CTCs) and paired circulating tumor DNA (ctDNA) samples of breast cancer patients. Cancer Research. 2017;77(13 Supplement):1725-.Google Scholar
  63. 63.
    Schiavon G, Hrebien S, Garcia-Murillas I, Pearson A, Tarazona N, Lopez-Knowles E, et al. Abstract 926: ESR1 mutations evolve during the treatment of metastatic breast cancer, and detection in ctDNA predicts sensitivity to subsequent hormone therapy. Cancer Res. 2015;75(15 Supplement):926.Google Scholar
  64. 64.
    Turner NC, Jiang Y, O'Leary B, Hrebien S, Cristofanilli M, Andre F, et al. Efficacy of palbociclib plus fulvestrant (P+F) in patients (pts) with metastatic breast cancer (MBC) and ESR1 mutations (mus) in circulating tumor DNA (ctDNA). Journal of Clinical Oncology. 2016;34(15_suppl):512-.Google Scholar
  65. 65.
    Baird RD, Rossum AV, Oliveira M, Beelen K, Garcia-Corbacho J, Mandjes IAM, et al. POSEIDON trial phase 1b results: Safety and preliminary efficacy of the isoform selective PI3K inhibitor taselisib (GDC-0032) combined with tamoxifen in hormone receptor (HR) positive, HER2-negative metastatic breast cancer (MBC) patients (pts) - including response monitoring by plasma circulating tumor (ct) DNA. Journal of Clinical Oncology. 2016;34(15_suppl):2520-.Google Scholar
  66. 66.
    Baselga J, Im S-A, Iwata H, Clemons M, Ito Y, Awada A, et al. Abstract S6–01: <em>PIK3CA</em> status in circulating tumor DNA (ctDNA) predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal women with endocrine-resistant HR+/HER2– advanced breast cancer (BC): First results from the randomized, phase III BELLE-2 trial. Cancer Res 2016;76(4 upplement):S6–01-S6-.Google Scholar
  67. 67.
    Bosch A, Li Z, Bergamaschi A, Ellis H, Toska E, Prat A, et al. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor–positive breast cancer. Science translational medicine. 2015;7(283):283ra51-ra51.Google Scholar
  68. 68.
    Oshiro C, Kagara N, Naoi Y, Shimoda M, Shimomura A, Maruyama N, et al. PIK3CA mutations in serum DNA are predictive of recurrence in primary breast cancer patients. Breast Cancer Res Treat. 2015;150(2):299–307.PubMedGoogle Scholar
  69. 69.
    Garcia-Murillas I, Schiavon G, Weigelt B, Ng C, Hrebien S, Cutts RJ, et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med 2015;7(302):302ra133-302ra133.Google Scholar
  70. 70.
    Ma C, Bose R, Gao F, Freedman R, Telli M, Kimmick G, et al. Abstract CT011: Circulating tumor DNA (ctDNA) sequencing for <em>HER2</em> mutation (<em>HER2</em><sup>mut</sup>) screening and response monitoring to neratinib in metastatic breast cancer (MBC). Cancer Res 2017;77(13 Supplement):CT011-CT.Google Scholar
  71. 71.
    Qiu M, Wang J, Xu Y, Ding X, Li M, Jiang F, et al. Circulating tumor DNA is effective for the detection of EGFR mutation in non–small cell lung Cancer: a meta-analysis. Cancer Epidemiology Biomarkers &amp; Prevention. 2014.Google Scholar
  72. 72.
    Goto T, Hirotsu Y, Amemiya K, Nakagomi T, Shikata D, Yokoyama Y, et al. Distribution of circulating tumor DNA in lung cancer: analysis of the primary lung and bone marrow along with the pulmonary venous and peripheral blood. Oncotarget. 2017;8(35):59268–81.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Hirsch FR, Varella-Garcia M, Bunn Jr PA, Franklin WA, Dziadziuszko R, Thatcher N, et al. Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non–small-cell lung cancer. J Clin Oncol. 2006;24(31):5034–42.PubMedGoogle Scholar
  74. 74.
    Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7(3):169.PubMedGoogle Scholar
  75. 75.
    Bai H, Wang Z, Chen K, Zhao J, Lee JJ, Wang S, et al. Influence of chemotherapy on EGFR mutation status among patients with non–small-cell lung cancer. J Clin Oncol. 2012;30(25):3077–83.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Overman MJ, Modak J, Kopetz S, Murthy R, Yao JC, Hicks ME, et al. Use of research biopsies in clinical trials: are risks and benefits adequately discussed? J Clin Oncol. 2012;31(1):17–22.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Normanno N, Denis MG, Thress KS, Ratcliffe M, Reck M. Guide to detecting epidermal growth factor receptor (EGFR) mutations in ctDNA of patients with advanced non-small-cell lung cancer. Oncotarget. 2017;8(7):12501–16.PubMedGoogle Scholar
  78. 78.
    Henick BS, Goldberg SB, Narayan A, Rossi C, Rodney S, Kole AJ, et al. Circulating tumor DNA (ctDNA) to monitor treatment response and progression in patients treated with tyrosine kinase inhibitors (TKIs) and immunotherapy for EGFR-mutant non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2017;Google Scholar
  79. 79.
    De Mattos-Arruda L, Cortes J, Santarpia L, Vivancos A, Tabernero J, Reis-Filho JS, et al. Circulating tumour cells and cell-free DNA as tools for managing breast cancer. Nat Rev Clin Oncol. 2013;10(7):377–89.PubMedGoogle Scholar
  80. 80.
    Wang S, Han X. Hu X, Wang X, Zhao L, tang L, et al. clinical significance of pretreatment plasma biomarkers in advanced non-small cell lung cancer patients. Clin Chim Acta. 2014;430:63–70.PubMedGoogle Scholar
  81. 81.
    Jing C-W, Wang Z, Cao H-X, Ma R, Wu J-Z. High resolution melting analysis for epidermal growth factor receptor mutations in formalin-fixed paraffin-embedded tissue and plasma free DNA from non-small cell lung cancer patients. Asian Pac J Cancer Prev. 2013;14(11):6619–23.Google Scholar
  82. 82.
    Zhang H, Liu D, Li S, Zheng Y, Yang X, Li X, et al. Comparison of EGFR signaling pathway somatic DNA mutations derived from peripheral blood and corresponding tumor tissue of patients with advanced non-small-cell lung cancer using liquidchip technology. The Journal of Molecular Diagnostics. 2013;15(6):819–26.PubMedGoogle Scholar
  83. 83.
    Yeung KT, More S, Woodward B, Velculescu V, Husain H. Circulating tumor DNA for mutation detection and identification of mechanisms of resistance in non-small cell lung Cancer. Molecular Diagnosis & Therapy. 2017;21(4):375–84.Google Scholar
  84. 84.
    Audibert C, Shea M, Glass D, Kozak M, Caze A, Hohman R, et al. Use of FDA-approved vs. lab-developed tests in advanced non-small cell lung cancer. Proc Am Soc Clin Oncol. 2016;e20532.
  85. 85.
    Nygaard AD, Garm Spindler K-L, Pallisgaard N, Andersen RF, Jakobsen A. The prognostic value of KRAS mutated plasma DNA in advanced non-small cell lung cancer. Lung Cancer. 2013;79(3):312–7.PubMedGoogle Scholar
  86. 86.
    Sherwood JL, Corcoran C, Brown H, Sharpe AD, Musilova M, Kohlmann A. Optimised pre-analytical methods improve KRAS mutation detection in circulating tumour DNA (ctDNA) from patients with non-small cell lung cancer (NSCLC). PLoS One. 2016;11(2):e0150197.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Paweletz CP, Oxnard GR, Feeney N, Hilton JF, Gandhi L, Do KT, et al. Abstract 3157: Serial droplet digital PCR (ddPCR) of plasma cell-free DNA (cfDNA) as pharmacodynamic (PD) biomarker in Phase 1 clinical trials for patients (pts) with KRAS mutant non-small cell lung cancer (NSCLC). Cancer Res. 2016;76(14 Supplement):3157-.Google Scholar
  88. 88.
    Bardelli A. Medical research: personalized test tracks cancer relapse. Nature. 2017;545(7655):417–8.PubMedGoogle Scholar
  89. 89.
    Geva S, Rozenblum AB, Ilouze M, Roisman L, Twito T, Dvir A, et al. P2.03b-047 the clinical impact of multiplex ctDNA Gene analysis in lung cancer. Journal of Thoracic Oncology. 12(1):S964.Google Scholar
  90. 90.
    Chabon JJ, Simmons AD, Lovejoy AF, Esfahani MS, Newman AM, Haringsma HJ, et al. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun. 2016;7:11815.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Merriott DJ, Chaudhuri AA, Jin M, Chabon JJ, Newman A, Stehr H, et al. circulating tumor dna quantitation for early response assessment of immune checkpoint inhibitors for lung cancer. Int J Radiat Oncol Biol Phys. 99(2):S20–S1.Google Scholar
  92. 92.
    Khatami F, Larijani B, Heshmat R, Keshtkar A, Mohammadamoli M, Teimoori-Toolabi L, et al. Meta-analysis of promoter methylation in eight tumor-suppressor genes and its association with the risk of thyroid cancer. PLoS One. 2017;12(9):e0184892.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Cai X, Gao Y, Shen H, Laird P, Fan, J-B, Xu W, et al. Non-invasive diagnosis of early-stage lung cancer via targeted high-throughput DNA methylation sequencing of circulating tumor DNA (ctDNA). AACR; 2017.Google Scholar
  94. 94.
    Pantel K, Alix-Panabieres C. Liquid biopsy in 2016: circulating tumour cells and cell-free DNA in gastrointestinal cancer. Nat Rev Gastroenterol Hepatol. 2017;14(2):73–4.PubMedGoogle Scholar
  95. 95.
    Yan W, Zhang A, Powell MJ. Genetic alteration and mutation profiling of circulating cell-free tumor DNA (cfDNA) for diagnosis and targeted therapy of gastrointestinal stromal tumors. Chinese journal of cancer. 2016;35(1):68.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Sotoudeh M, Derakhshan MH, Abedi-Ardakani B, Nouraie M, Yazdanbod A, Tavangar SM, et al. Critical role of helicobacter pylori in the pattern of gastritis and carditis in residents of an area with high prevalence of gastric cardia cancer. Dig Dis Sci. 2008;53(1):27–33.PubMedGoogle Scholar
  97. 97.
    Malekzadeh R, Sotoudeh M, Derakhshan M, Mikaeli J, Yazdanbod A, Merat S, et al. Prevalence of gastric precancerous lesions in Ardabil, a high incidence province for gastric adenocarcinoma in the northwest of Iran. J Clin Pathol. 2004;57(1):37–42.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Szpechcinski A, Chorostowska-Wynimko J, Struniawski R, Kupis W, Rudzinski P, Langfort R, et al. Cell-free DNA levels in plasma of patients with non-small-cell lung cancer and inflammatory lung disease. Br J Cancer. 2015;113(3):476.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Shapiro B, Chakrabarty M, Cohn EM, Leon SA. Determination of circulating DNA levels in patients with benign or malignant gastrointestinal disease. Cancer. 1983;51(11):2116–20.PubMedGoogle Scholar
  100. 100.
    De Mattos-Arruda L, Olmos D, Tabernero J. Prognostic and predictive roles for circulating biomarkers in gastrointestinal cancer. Future Oncol. 2011;7(12):1385–97.PubMedGoogle Scholar
  101. 101.
    Howell JA, Khan SA, Knapp S, Thursz MR, Sharma R. The clinical role of circulating free tumor DNA in gastrointestinal malignancy. Transl Res. 2017;183(Supplement C):137–54.PubMedGoogle Scholar
  102. 102.
    Nasseri-Moghaddam S, Malekzadeh R, Sotoudeh M, Tavangar M, Azimi K, Sohrabpour AA, et al. Lower esophagus in dyspeptic Iranian patients: a prospective study. J Gastroenterol Hepatol. 2003;18(3):315–21.PubMedGoogle Scholar
  103. 103.
    Schwarzenbach H, Stoehlmacher J, Pantel K, Goekkurt E. Detection and monitoring of cell-free DNA in blood of patients with colorectal Cancer. Ann N Y Acad Sci. 2008;1137(1):190–6.PubMedGoogle Scholar
  104. 104.
    Boni L, Cassinotti E, Canziani M, Dionigi G, Rovera F, Dionigi R. Free circulating DNA as possible tumour marker in colorectal cancer. Surg Oncol. 2007;16:29–31.Google Scholar
  105. 105.
    Frattini M, Gallino G, Signoroni S, Balestra D, Battaglia L, Sozzi G, et al. Quantitative analysis of plasma DNA in colorectal cancer patients. Ann N Y Acad Sci. 2006;1075(1):185–90.PubMedGoogle Scholar
  106. 106.
    Frattini M, Gallino G, Signoroni S, Balestra D, Lusa L, Battaglia L, et al. Quantitative and qualitative characterization of plasma DNA identifies primary and recurrent colorectal cancer. Cancer Lett. 2008;263(2):170–81.PubMedGoogle Scholar
  107. 107.
    Danese E, Montagnana M, Minicozzi AM, De Matteis G, Scudo G, Salvagno GL, et al. Real-time polymerase chain reaction quantification of free DNA in serum of patients with polyps and colorectal cancers. Clin Chem Lab Med. 2010;48(11):1665–8.PubMedGoogle Scholar
  108. 108.
    Hedtke M, Haselmann V, Brechtel I, Duda A, Neumaier M. Use of liquid profiling/liquid biopsy to detect Ras mutations in cfdna of patients with metastatic colorectal cancer (mcrc). Clinical Chemistry and Laboratory Medicine. 2016;54(10):eA441.Google Scholar
  109. 109.
    Tavangar SM, Shariftabrizi A, Soroush AR. Her–2/neu over-expression correlates with more advanced disease in Iranian colorectal cancer patients. Med Sci Monit. 2005;11(3):CR123–CR6.PubMedGoogle Scholar
  110. 110.
    Pereira AAL, Morelli MP, Overman M, Kee B, Fogelman D, Vilar E, et al. Clinical utility of circulating cell-free DNA in advanced colorectal cancer. PLoS One. 2017;12(8):e0183949.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Spindler K-LG, Pallisgaard N, Vogelius I, Jakobsen A, Quantitative cell free DNA. KRAS and BRAF mutations in plasma from patients with metastatic colorectal cancer during treatment with cetuximab and irinotecan. Clinical Cancer research. 2012:clincanres. 2011:0564.Google Scholar
  112. 112.
    Reinert T, Schøler LV, Thomsen R, Tobiasen H, Vang S, Nordentoft I, et al. Analysis of circulating tumour DNA to monitor disease burden following colorectal cancer surgery. Gut. 2016;65(4):625–34.PubMedGoogle Scholar
  113. 113.
    Lipson EJ, Velculescu VE, Pritchard TS, Sausen M, Pardoll DM, Topalian SL, et al. Circulating tumor DNA analysis as a real-time method for monitoring tumor burden in melanoma patients undergoing treatment with immune checkpoint blockade. Journal for immunotherapy of cancer. 2014;2(1):42.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Chen W, Zheng R, Zhang S, Zhao P, Li G, Wu L, et al. The incidences and mortalities of major cancers in China, 2009. Chinese journal of cancer. 2013;32(3):106.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Bass AJ, Thorsson V, Shmulevich I, Reynolds SM, Miller M, Bernard B, et al. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202.PubMedCentralGoogle Scholar
  116. 116.
    Zhang W. TCGA divides gastric cancer into four molecular subtypes: implications for individualized therapeutics. Chinese journal of cancer. 2014;33(10):469.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Nishida T, Biological HS. Clinical review of stromal tumors in the gastrointestinal tract. Histol Histopathol. 2000;15(4):1293–301.PubMedGoogle Scholar
  118. 118.
    Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011;11(12):865.PubMedGoogle Scholar
  119. 119.
    Lourenço N, Hélias-Rodzewicz Z, Bachet J-B, Brahimi-Adouane S, Jardin F, van Nhieu JT, et al. Copy-neutral loss of heterozygosity and chromosome gains and losses are frequent in gastrointestinal stromal tumors. Mol Cancer. 2014;13(1):246.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Astolfi A, Nannini M, Pantaleo MA, Di Battista M, Heinrich MC, Santini D, et al. A molecular portrait of gastrointestinal stromal tumors: an integrative analysis of gene expression profiling and high-resolution genomic copy number. Lab Investig. 2010;90(9):1285–94.PubMedGoogle Scholar
  121. 121.
    Nannini M, Astolfi A, Urbini M, Indio V, Santini D, Heinrich MC, et al. Integrated genomic study of quadruple-WT GIST (KIT/PDGFRA/SDH/RAS pathway wild-type GIST). BMC Cancer. 2014;14(1):685.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Gronchi A. Risk stratification models and mutational analysis: keys to optimising adjuvant therapy in patients with gastrointestinal stromal tumour. Eur J Cancer. 2013;49(4):884–92.PubMedGoogle Scholar
  123. 123.
    Şendur MAN, Özdemir NY, Akıncı MB, Uncu D, Zengin N, Aksoy S. Is exon mutation analysis needed for adjuvant treatment of gastrointestinal stromal tumor? World J Gastroenterol: WJG. 2013;19(1):144–6.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Wada N, Kurokawa Y, Takahashi T, Hamakawa T, Hirota S, Naka T, et al. Detecting secondary C-KIT mutations in the peripheral blood of patients with imatinib-resistant gastrointestinal stromal tumor. Oncology. 2016;90(2):112–7.PubMedGoogle Scholar
  125. 125.
    Boonstra PA, At E, Tibbesma M, Mathijssen RH, Atrafi F, Fv C, et al. Abstract 4951: dynamics of KIT exon 11 mutations in cell free plasma DNA of patients treated for advanced gastrointestinal stromal tumors: results from the Dutch GIST bio-databank. Cancer Res. 2017;77(13 Supplement):4951.Google Scholar
  126. 126.
    Maier J, Lange T, Kerle I, Specht K, Bruegel M, Wickenhauser C,et al. Detection of mutant free circulating tumor DNA in the plasma of patients with gastrointestinal stromal tumor harboring activating mutations of CKIT or PDGFRA. Clin Cancer Res. 2013;0765.
  127. 127.
    Lan Y-T, Chen M-H, Fang W-L, Hsieh C-C, Lin C-H, Jhang F-Y, et al. Clinical relevance of cell-free DNA in gastrointestinal tract malignancy. Oncotarget. 2017;8(2):3009–17.PubMedGoogle Scholar
  128. 128.
    Fallahi P, Giannini R, Miccoli P, Antonelli A, Basolo F. Molecular diagnostics of fine needle aspiration for the presurgical screening of thyroid nodules. Current genomics. 2014;15(3):171–7.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Tavangar SM, Monajemzadeh M, Larijani B, Haghpanah V. Immunohistochemical study of oestrogen receptors in 351 human thyroid glands. Singap Med J. 2007;48(8):744–7.Google Scholar
  130. 130.
    Saffar H, Sanii S, Emami B, Heshmat R, Panah VH, Azimi S, et al. Evaluation of MMP2 and Caspase-3 expression in 107 cases of papillary thyroid carcinoma and its association with prognostic factors. Pathol Res Pract. 2013;209(3):195–9.PubMedGoogle Scholar
  131. 131.
    Sanii S, Tavangar SM. Cutaneous metastasis of medullary thyroid carcinoma as the initial manifestation of an otherwise limited malignancy: a case report. Am J Dermatopathol. 2011;33(7):716–8.PubMedGoogle Scholar
  132. 132.
    Haghpanah V, Abbas SI, Mahmoodzadeh H, Shojaei A, Soleimani A, Larijani B, et al. Paraplegia as initial presentation of follicular thyroid carcinoma. Journal of the College of Physicians and Surgeons--Pakistan : JCPSP. 2006;16(3):233–4.PubMedGoogle Scholar
  133. 133.
    Janku F, Huang HJ, Ramzanali NM, Hong DS, Karp DD. Fu S, et al. ultra-deep next-generation sequencing of plasma cell-free (cf) DNA from patients with advanced cancers. Proc Am Soc Clin Oncol. 2015;Google Scholar
  134. 134.
    Sandulache VC, Williams MD, Lai SY, Lu C, William WN, Busaidy NL, et al. Real-time genomic characterization utilizing circulating cell-free DNA in patients with anaplastic thyroid carcinoma. Thyroid. 2017;27(1):81–7.PubMedPubMedCentralGoogle Scholar
  135. 135.
    Bible KC, Ryder M. Evolving molecularly targeted therapies for advanced-stage thyroid cancers. Nat Rev Clin Oncol. 2016;13(7):403–16.PubMedGoogle Scholar
  136. 136.
    Cote GJ, Evers C, Hu MI, Grubbs EG, Williams MD, Hai T, et al. Prognostic significance of circulating RET M918T mutated tumor DNA in patients with advanced medullary thyroid carcinoma. The Journal of Clinical Endocrinology & Metabolism. 2017;102(9):3591–9.Google Scholar
  137. 137.
    Brose MS, Cabanillas ME, Cohen EE, Wirth LJ, Riehl T, Yue H, et al. Vemurafenib in patients with BRAF V600E-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. The Lancet Oncology. 2016;17(9):1272–82.PubMedPubMedCentralGoogle Scholar
  138. 138.
    Khatami F, Larijani B, Tavangar SM. Circulating tumor BRAF mutation and personalized thyroid Cancer treatment. Asian Pacific journal of cancer prevention: APJCP. 2017;18(2):293–4.PubMedPubMedCentralGoogle Scholar
  139. 139.
    Patel KB. Detection of circulating thyroid tumor DNA in patients with thyroid nodules. 2015.Google Scholar
  140. 140.
    Dakubo GD. Endocrine Cancer biomarkers in circulation. Cancer Biomarkers in Body Fluids: Springer; 2017. p. 457–80.Google Scholar
  141. 141.
    Pereira E, Camacho-Vanegas O, Anand S, Sebra R, Camacho SC, Garnar-Wortzel L, et al. Personalized circulating tumor DNA biomarkers dynamically predict treatment response and survival in gynecologic cancers. PLoS One. 2015;10(12):e0145754.PubMedPubMedCentralGoogle Scholar
  142. 142.
    Kajbafzadeh A-M, Payabvash S, Salmasi AH, Monajemzadeh M, Tavangar SM. Smooth muscle cell apoptosis and defective neural development in congenital ureteropelvic junction obstruction. J Urol. 2006;176(2):718–23.PubMedGoogle Scholar
  143. 143.
    Kamat AA, Sood AK, Dang D, Gershenson DM, Simpson JL, Bischoff FZ. Quantification of total plasma cell-free DNA in ovarian cancer using real-time PCR. Ann N Y Acad Sci. 2006;1075(1):230–4.PubMedGoogle Scholar
  144. 144.
    Harris FR, Kovtun IV, Smadbeck J, Multinu F, Jatoi A, Kosari F, et al. Quantification of somatic chromosomal rearrangements in circulating cell-free DNA from ovarian cancers. Sci Rep. 2016;6:29831.PubMedPubMedCentralGoogle Scholar
  145. 145.
    Sarmadi S, Izadi-Mood N, Sotoudeh K, Tavangar SM. Altered PTEN expression; a diagnostic marker for differentiating normal, hyperplastic and neoplastic endometrium. Diagn Pathol. 2009;4(1):41.PubMedPubMedCentralGoogle Scholar
  146. 146.
    Arend RC, Londono AI, Alvarez RD, Huh WK, Bevis KS, Leath CA, et al., editors. Circulating cell-free DNA: The future of personalized medicine in ovarian cancer management. Journal of Clinical Oncology; 2016: AMER SOC CLINICAL ONCOLOGY 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA.Google Scholar
  147. 147.
    Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. The Lancet Oncology. 2016;17(4):425–39.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences InstituteTehran University of Medical SciencesTehranIran
  2. 2.Departments of Pathology, Doctor Shariati HospitalTehran University of Medical SciencesTehranIran

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